This renewal application proposes to continue the development of new organic reactions for the facilitated synthesis of [3.2.1]bicyclic compounds including vitisinol D, a resveratrol natural product. As part of our activities in the current grant cycle, we have so far nearly completed (a single step remaining) the first total synthesis of this natural product. The synthesis plan involved the application of relatively new and underutilized building blocks in organic chemistry (chiral allenyl esters) exploiting the high degree of unsaturation and unique juxtaposition of functional groups present. In this period, we propose a new route to vitisinol D that will significantly reduce the number of steps (from 14 to 7) and further exploit the potential of allene chemistry. Importantly, the planned synthesis will make available sufficient quantities of this structurally unique and virtually inaccessible natural product to enable biological studies to determine their potential as neuroprotective agents. The project will also expand methods to prepare more complex allenyl esters as single isomers (non- racemic). These methods entail the development of unique catalysts (chiral catechols) to afford a high degree of control in bond formation leading to the functionalized allenyl ester products. With these allene building blocks in hand, a series of vitisinol D derivatives will be efficiently synthesized (3-5 steps). Through a collaboration with a member of our Biology Department, the neuroprotective activity of vitisinol D and its derivatives will be examined in a highly efficient fruit fly model. Our ongoing collaborative efforts reveal that polyphenol compounds such as resveratrol act via a specific mechanism unrelated to the known antioxidant properties of these compounds. Thus, biological studies in this renewal project, enabled by the synthesis methods developed, will entail a search for specific neuroprotective mechanisms of our active compounds. These studies will ultimately serve as a starting point for future medicinal chemistry investigations to identify novel agents against diseases such as Parkinson's and stroke